Quinoline derivatives as anti-inflammatory agents

ABSTRACT

This invention relates to compounds, which are generally anti-inflammatory and analgesic compounds, and which are represented by Formula I: 
                         
wherein A is a CH 2 , CH(OH), C(O), C═NOR 4 , NR 5 , O, S, S(O), or S(O) 2 , and the other substituents are as defined in the specification; or prodrugs, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a division of U.S. Ser. No. 09/925,883, filed Aug.7, 2001, now U.S. Pat. No. 7,049,325 and claims priority from benefitfrom U.S. Ser. No. 60/224,196 filed Aug. 9, 2000; incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to anti-inflammatory and analgesic compounds,especially to certain quinoline derivatives, pharmaceutical compositionscontaining them, methods for their use, and methods for preparing thesecompounds.

Non-steroidal, antiinflammatory drugs (NSAIDs), have a problem ofcausing serious side-effects such as gastrointestinal tract ornephro-toxicity. NSAIDs inhibit the activity of cyclooxygenase (COX),which is an enzyme involved in prostaglandin G/H synthesis, resulting inthe inhibition of the biosynthesis of prostaglandins not only ininflammatory loci but also in stomach and kidney. It has been found thatCOX exists in two forms: COX-1 and COX-2, Cell, 83, 345, (1995).

COX-1 is expresed in normal cells and controls the function of stomachand kidney, while COX-2 is induced by mitogens or cytokines ininflammatory sites where inflammation and other immunoreactions occur,J. Biol. Chem., 271, 33157(1996).

To avoid the toxicity of NSAIDs due to the inhibition of coexistingCOX-1, selective inhibitors of COX-2 have been investigated. Theselective COX-2 inhibitors have antiinflammatory action, pain-relievingaction, and/or antipyretic action; with less side effects, such asbleeding in the gastrointestinal tract, COX-2 inhibitors may showanticancer activity, and lower the induction of asthma in asthmaticpatients who are sensitive to conventional NSAIDs. These selectiveinhibitors of COX-2 may also be used in treating Alzheimer's disease andosteoporosis of women after menopause.

2. Description of Related Art

-   U.S. Pat. No. 6,077,850 (G. D. Searle) discloses    1,2-dihydroquinoline derivatives for use in treating    cyclooxygenase-2 mediated disorders.-   U.S. Pat. No. 6,069,151 (Darwin Discovery, Ltd.) discloses    quinolines and their therapeutic usee.-   U.S. Pat. No. 5,962,531 (Syntex USA, Inc) discloses    5-aroylnaphthalene derivatives as anti-inflammatory agents.-   U.S. Pat. No. 5,221,677 (Imperial Chemical Industries PLC) discloses    quinoline or isoquinoline derivatives as 5-lipoxygenase inhibitors.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides compounds selected from thegroup of compounds represented by Formula I:

wherein:

A is a CH₂, CH(OH), C(O), C═NOR⁴, NR⁵, O, S, S(O), or S(O)₂ where R⁴ ishydrogen or alkyl and R⁵ is hydrogen, alkyl, or acyl;

Ar is an optionally substituted phenyl;

R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,cycloalkyl, cycloalkylalkyl, alkoxy, alkenyloxy, cycloalkyloxy,cycloalkylalkyloxy, haloalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy,alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylthio,cycloalkylalkylthio, hydroxy, halo, cyano, —NR⁹R¹⁰, —OCONR⁹R¹⁰, or—OSO₂R¹¹ where R⁹ and R¹⁰ are each independently selected from hydrogen,alkyl, and acyl; and R¹¹ is selected from alkyl, cycloalkyl, andhaloalkyl;

R² is hydrogen, alkyl, alkenyl, alkoxy, hydroxy, halo, haloalkyl,heteroalkyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, nitro, cyano,or —NR⁹R¹⁰ where R⁹ and R¹⁰ are each independently selected form therespective gorup described for R⁹ and R¹⁰ previously; it is understoodthat, as indicated in Formula I, R² represents substitution of any oneof carbons C3, C4, C7 or C8;

R³ is —SR¹², —SOR¹², —SO₂R¹², or —SO₂NR¹³R¹⁴ wherein

-   -   R¹² is alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono or        dialkylaminoalkyl, carboxyalkyl, or alkoxycarbonylalkyl;    -   R¹³ is hydrogen or alkyl, and    -   R¹⁴ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,        hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, aminoalkyl,        aryl, or aralkyl; or R¹³ and R¹⁴ together with the

nitrogen atom to which they are attached form a heterocycloamino group;and prodrugs, individual isomers, mixtures of isomers, andpharmaceutically acceptable salts thereof.

In a second aspect, this invention provides pharmaceutical compositionscontaining a therapeutically effective amount of a compound of Formula Ior its pharmaceutically acceptable salt and a pharmaceuticallyacceptable excipient.

In a third aspect, this invention provides a method of treatment of adisease, in particular an inflammatory and autoimmune disease, in amammal treatable by administration of a prostaglandin G/H synthaseinhibitor, comprising administration of a therapeutically effectiveamount of a compound of Formula I or its pharmaceutically acceptablesalt.

In a fourth aspect, this invention provides processes for preparingcompounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

“Acyl” means the group —C(O)R′, where R′ is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl, wherein the phenyl group can beoptionally substituted.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl,2-propyl, tert-butyl, pentyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene, propylene,2-methylpropylene, pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means a radical—OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively,as defined herein, e.g., methoxy, phenoxy, benzyloxy,pyridin-2-ylmethyloxy, and the like.

“Alkoxycarbonylalkyl” means a radical —R^(a)C(O)R^(b) where R^(a) is analkylene group as defined above and R^(b) is an alkoxy group as definedabove e.g., methoxycarbonylethyl, ethoxycarbonylbutyl, and the like.

“Alkylsulfanyl” or “alkylthio” means a radical —SR where R is hydrogenor alkyl as defined herein, e.g., methylsulfanyl, ethylsulfanyl, and thelike.

“Alkylsulfinyl” means a radical —S(O)R where R is hydrogen or alkyl asdefined herein, e.g., methylsulfinyl, ehtylsulfinyl, and the like.

“Alkylsulfonyl” means a radical —S(O)₂R where R is hydrogen or alkyl asdefined herein, e.g., methylsulfonyl, ehtylsulfonyl, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic radical of 6to 10 ring atoms which is substituted independently with one to fivesubstituents, preferably one, two, or three substituents selected fromalkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy,amino, acylamino, alkylamino, dialkylamino, haloalkyl, haloalkoxy,heteroalkyl, —COR (where R is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—COOR (where n isan integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl,and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl) or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a) and R^(b)are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl). More specifically the term arylincludes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and2-naphthyl, and the derivatives thereof.

“Aralkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylene groupand R^(b) is an aryl group as defined herein, e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like.

“Aralkenyl” means a radical —R^(a)R^(b) where R^(a) is an alkenylenegroup and R^(b) is an aryl group as defined herein, e.g.,3-phenyl-2-propenyl, and the like.

“Cycloalkyl” means a saturated monovalent cyclic hydrocarbon radical ofthree to seven ring carbons. The cycloalkyl may be optionallysubstituted independently with one, two, or three substituents selectedfrom alkyl, optionally substituted phenyl, or —C(O)R (where R ishydrogen, alkyl, haloalkyl, amino, acylamino, mono-alkylamino,di-alkylamino, hydroxy, alkoxy, or optionally substituted phenyl). Morespecifically, the term cycloalkyl includes, for example, cyclopropyl,cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl,2-carboxamidocyclohexyl, 2-dimethylaminocarbonyl-cyclohexyl, and thelike.

“Cycloalkylalkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a cycloalkyl group as defined herein, e.g.,cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, andthe like.

“Haloalkyl” means alkyl substituted with one or more same or differenthalogen atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like, andfurther includes those alkyl groups such as perfluoroalkyl in which allhydrogen atoms are replaced by fluorine atoms.

“Heteroalkyl” means an alkyl radical as defined herein with one, two orthree substituents independently selected from —OR^(a), —NR^(b)R^(c),and —S(O)_(n)R^(d) (where n is an integer from 0 to 2 ), with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom of the heteroalkyl radical. R^(a) is hydrogen,alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl,aryloxycarbonyl, or carboxamido. R^(b) is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl or aralkyl. R^(c) is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl,carboxamido, mono- or dialkylcarbamoyl or alkylsulfonyl. R^(d) ishydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, amino, monoalkylamino, dialkylamino, or hydroxyalkyl.Representative examples include, for example, 2-hydroxyethyl,2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl,2-methylsulfonyl-ethyl.

“Hydroxyalkyl” means an alkyl radical as defined herein, substitutedwith one or more, preferably one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxymethyl-2-methylpropyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,1-hydroxymethyl-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyland 2-hydroxymethyl-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-hydroxymethyl-2-hydroxyethyl. Accordingly, asused herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

“Optionally substituted phenyl” means a phenyl ring which is optionallysubstituted independently with one to four substituents, preferably oneor two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl,halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino,dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR (where R ishydrogen, alkyl, phenyl or phenylalkyl, —(CR′R″)_(n)—COOR (where n is aninteger from 0 to 5, R′ and R″ are independently hydrogen or alkyl, andR is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a) andR^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl).

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry i.e., an atom or group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo,iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than-onesuch excipient.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

-   -   (1) acid addition salts, formed with inorganic acids such as        hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,        phosphoric acid, and the like; or formed with organic acids such        as acetic acid, propionic acid, hexanoic acid,        cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic        acid, malonic acid, succinic acid, malic acid, maleic acid,        fumaric acid, tartaric acid, citric acid, benzoic acid,        3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,        methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic        acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,        4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,        4-toluenesulfonic acid, camphorsulfonic acid,        4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid,        glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic        acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid,        glutamic acid, hydroxynahthoic acid, salicylic acid, stearic        acid, muconic acid, and the like; or    -   (2) salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic base such as ethanolamine,        diethanolamine, triethanolamine, tromethamine,        N-methylglucamine, and the like.

“Prodrugs” means any compound which releases an active parent drugaccording to Formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula I are prepared bymodifying functional groups present in the compound of Formula I in sucha way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of Formula I wherein ahydroxy, amino, or sulfhydryl group in a compound of Formula I is bondedto any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy functional groups in compounds of Formula I, and the like.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Futs, Protective Groups in Organic Chemistry, (Wiley, 2nd ed. 1991) andHarrison and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1–8 (John Wiley and Sons. 1971–1996). Representative aminoprotecting groups include formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl(TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), and the like. Representative hydroxyprotecting groups include those where the hydroxy group is eitheracylated or alkylated such as benzyl and trityl ethers, as well as alkylethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allylethers.

“Treating” or “treatment” of a disease includes:

-   -   (1) preventing the disease, i.e. causing the clinical symptoms        of the disease not to develop in a mammal that may be exposed to        or predisposed to the disease but does not yet experience or        display symptoms of the disease,    -   (2) inhibiting the disease, i.e., arresting or reducing the        development of the disease or its clinical symptoms, or    -   (3) relieving the disease, i.e., causing regression of the        disease or its clinical symptoms.

“A therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

“Optional” or “optionally” in the above definitions means that thesubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “heterocyclogroup optionally mono- or di substituted with an alkyl group” means thatthe alkyl may but need not be present, and the description includessituations where the heterocyclo group is mono- or disubstituted with analkyl group and situations where the heterocyclo group is notsubstituted with the alkyl group.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn, Ingold and Prelog, (Cahn et al. Angew. Chem. Inter. Edit., 5, 385;(1966) errata 511; Cahn et al. Angew. Chem., 78, 413;(1966) Cahn andIngold J. Chem. Soc. (London), 612; (1951) Cahn et al. Experientia, 12,81;(1956), Cahn, J. Chem.Educ., 41, 116, (1964)) or by the manner inwhich the molecule rotates the plane of polarized light and designatedas dextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either an individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The compounds of this invention may exist in stereoisomeric form if theypossess one or more asymmetric centers. In addition, double bondspresent in compounds of this invention may be either the E or Zconfiguration. Unless otherwise indicated, the description is intendedto include individual stereoisomers as well as mixtures. Similarly, itis appreciated that the description includes individual double bondisomers as well as mixtures. The methods for the determination ofstereochemistry and the separation of stereoisomers are well-known inthe art (see discussion in Chapter 4 of “Advanced Organic Chemistry”,4th edition J. March, John Wiley and Sons, New York, 1992).

Througout the application the following abbreviations are used with thefollowing meanings:

DIBAL Diisobutylaluminum hydride

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EtOAc Ethyl Acetate

HMPA Hexamethylphosphoric triamide

HPLC High pressure liquid chromatography

MCPBA m-Chloroperbenzoic acid

MHz Megahertz

MS Mass Spectrum

NMR Nuclear Magnetic Resonance

OXONE™ Potassium peroxymonosulfate

PCC Pyridinium chlorochromate

PIFA Bis(trifluoroacetoxy)iodobenzene

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

Nonmenclature

The naming and numbering of the compounds of this invention isillustrated below.

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

Representative Compounds of this Invention are as Follows:

Compounds of Formula I wherein R¹, R², R³, A, and Ar are as definedbelow:

Cpd MS. # R¹ R² R³ A Ar [m + H]⁺ 102 methoxy H methylsulfonyl —S—4-fluorophenyl 364 103 methoxy H methylsulfonyl —S— 4-chlorophenyl 380104 methoxy H methylsulfonyl —S— 2-chlorophenyl 380 101 methoxy Hmethylsulfonyl —S— 2,4-difluorophenyl 382 105 methoxy H methylsulfonyl—S— 2-chloro-4- 398 fluorophenyl 106 methoxy H methylsulfonyl —S—4-bromophenyl 425 107 methoxy H methylsulfonyl —S— 2,4-dichlorophenyl415 202 methoxy H methylsulfonyl —C(O)— 2-chlorophenyl 376 201 methoxy Hmethylsulfonyl —C(O)— 4-methoxyphenyl 372 301 methoxy H methylsulfonyl—S(O)— 2,4-difluorophenyl 398 110 methoxy H methylsulfonyl —S—4-methoxyphenyl 376 108 methoxy H methylsulfonyl —S— 2,3,4,5,6- 436pentafluorophenyl 109 methoxy H methylsulfonyl —S— phenyl 346 401hydroxy H methylsulfonyl —S— 4-fluorophenyl 350 501 CF₃SO₂O— Hmethylsulfonyl —S— 4-fluorophenyl 482 111 methoxy H methylsulfonyl —S—2-fluoro-4- 394 methoxyphenyl 112 methoxy H methylsulfonyl —S—2-chloro-4- 410 methoxyphenyl 702 methoxy H methylsulfonyl —O—2-fluoro-4- 426 methanesulfonylphenyl 711 methoxy H methylsulfinyl —O—4-fluorophenyl 332 703 methoxy H methylsulfonyl —O— 4-fluorophenyl 348602 methoxy H methylsulfonyl —CH₂— 4-fluorophenyl 346 704 methoxy Hmethylsulfonyl —O— 2-chloro-4- 394 methoxyphenyl 601 methoxy Hmethylsulfonyl —CH₂— 2,4-difluorophenyl 364 609 methoxy H methylsulfinyl—CH₂— 2,4-difluorophenyl 348 701 methoxy H methylsulfonyl —O—2,4-difluorophenyl 366 603 methoxy H methylsulfonyl —CH₂— 4-ethoxyphenyl346 604 methoxy H methylsulfonyl —CH₂— 2-fluorophenyl 372 203 methoxy Hmethylsulfonyl —C(O)— 4-fluorophenyl 360 602 hydroxy H methylsulfonyl—CH₂— 4-fluorophenyl 332 606 methoxy H methylsulfonyl —CH₂—4-methoxyphenyl 358 605 methoxy H methylsulfonyl —CH₂— 4-methylphenyl342 607 methoxy H methylsulfonyl —CH₂— 4-chlorophenyl 362 113 methoxy Hmethylsulfonyl —S— 2-methoxy-4- 394 fluorophenyl 204 methoxy Hmethylsulfonyl —C(O)— 2-fluorophenyl 360 205 methoxy H methylsulfonyl—C(O)— 2,4,difluorophenyl 378 710 methoxy H methylsufinyl —O—2,4,difluorophenyl 350 705 methoxy H methylsulfonyl —O— 4-ethoxyphenyl374 706 methoxy H methylsulfonyl —O— phenyl 330 206 methoxy Hmethylsulfonyl —C(O)— 4-ethoxyphenyl 386 207 methoxy H methylsulfonyl—C(O)— 4-chlorophenyl 376 707 methoxy H methylsulfonyl —O—2-fluorophenyl 348 608 methoxy H methylsulfanyl —CH₂—2,4,-difluorophenyl 332 712 methoxy H methylsulfanyl —O—2,4,-difluorophenyl 334 114 methoxy H methylsulfonyl —S—2,6-difluorophenyl 382 211 methoxy H methylsulfinyl —C(O)—4-fluorophenyl 344 208 methoxy H methylsulfonyl —C(O)—3-chloro-2-fluoro-6- 424 methoxyphenyl 214 methoxy H methylsulfinyl—C(O)— 3-chloro-2-fluoro-6- 408 methoxyphenyl 708 methoxy Hmethylsulfonyl —O— 2,6-difluorophenyl 366 209 methoxy H methylsulfonyl—C(O)— 3-bromo-2,6- 457 difluorophenyl 210 methoxy H methylsulfonyl—C(O)— 2,6-difluorophenyl 378 212 methoxy H methylsulfinyl —C(O)—4-chlorophenyl 360 213 methoxy H methylsulfinyl —C(O)— 4-ethoxyphenyl370 709 methoxy H methylsulfonyl —O— 2-fluoro-6- 426 methanesulfonyl-phenylPreferred Embodiments

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula I are preferred.

A. In certain preferred embodiments A is —S—. Within the foregoingpreferred embodiment, another preferred group of compounds is thatwherein:

-   -   R¹ is alkyl, alkoxy, hydroxy, halogen, or cyano;    -   R²is hydrogen or methyl; and    -   R³ is S(O)₀₋₂R¹² where R¹² is alkyl.

Within the foregoing preferred embodiment, another preferred group ofcompounds is that wherein Ar is selected from the group consisting of anunsubstituted phenyl, a 4-substituted phenyl, and a 2-substitutedphenyl. An additional preferred group of compounds is that wherein Ar isa disubstituted phenyl, such as 2,4-disubstituted phenyl or3,4-disubstituted phenyl.

Within the foregoing preferred embodiment another preferred group ofcompounds is that wherein Ar is a phenyl optionally substituted at oneor mote positions, preferably with one to two substitutentsindependently selected from the group consisting of fluoro, chloro,bromo, ethoxy and methoxy.

B. In other preferred embodiments A is —C(O)—. Within the foregoingpreferred embodiment, another preferred group of compounds is thatwherein:

-   -   R¹ is alkyl, alkoxy, hydroxy, halogen or cyano;    -   R² is hydrogen or methyl; and    -   R³ is S(O)₀₋₂R¹² where R¹² is alkyl.

Within the foregoing preferred embodiment, another preferred group ofcompounds is that wherein Ar is selected from the group consisting of anunsubstituted phenyl, a 4-substituted phenyl, and a 2-substitutedphenyl. An additional preferred group of compounds is that wherein Ar isa disubstituted phenyl, such as 2,4-disubstituted phenyl or3,4-disubstituted phenyl.

Within the foregoing preferred embodiment another preferred group ofcompounds t is that wherein Ar is a phenyl optionally substituted at oneor more positions with a substitutent or substitutents independentlyselected from the group consisting of fluoro, chloro, bromo, ethoxy andmethoxy.

C. In additional preferred embodiments A is —O—. Within the foregoingpreferred embodiment, another preferred group of compounds is thatwherein:

-   -   R¹ is alkyl, alkoxy, hydroxy, halogen or cyano;    -   R² is hydrogen or methyl; and    -   R³ is S(O)₀₋₂R¹² where R¹² is alkyl.

Within the foregoing preferred embodiment, another preferred group ofcompounds is that wherein Ar is selected from the group consisting of anunsubstituted phenyl, a 4-substituted phenyl, and a 2-substitutedphenyl. An additional preferred group of compounds is that wherein Ar isa disubstituted phenyl, such as 2,4-disubstituted phenyl or3,4-disubstituted phenyl.

Within the foregoing preferred embodiment another preferred group ofcompounds is that wherein Ar is a phenyl optionally substituted at oneor more positions with a substitutent or substitutents independentlyselected from the group consisting of fluoro, chloro, bromo, ethoxy andmethoxy.

D. In additional preferred embodiments A is —CH₂—. Within the foregoingpreferred embodiment, another preferred group of compounds is thatwherein:

-   -   R¹ is alkyl, alkoxy, hydroxy, halogen or cyano;    -   R² is hydrogen or methyl; and    -   R³ is S(O)₀₋₂R¹² where R¹² is alkyl.

Within the foregoing preferred embodiment, another preferred group ofcompounds is that wherein Ar is selected from the group consisting of anunsubstituted phenyl, a 4-substituted phenyl, and a 2-substitutedphenyl. An additional preferred group of compounds is that wherein Ar isa disubstituted phenyl, such as 2,4-disubstituted phenyl or3,4-disubstituted phenyl.

Within the foregoing preferred embodiment another preferred group ofcompounds is that wherein Ar is a phenyl optionally substituted at oneor more positions with a substitutent or substitutents independentlyselected from the group consisting of fluoro, chloro, bromo, ethoxy andmethoxy.

E. In additional preferred embodiments, preferred compounds of Formula Iare those in which R¹ is hydroxy, alkoxy or alkyl, R² is hydrogen oralkyl, R³ is alkylsulfanyl, alkylsulfinyl or alkylsulfonyl, and Ar isunsubstituted, monosubstituted, or disubstituted phenyl. Even morepreferred are compounds of Formula I are those in which R¹ is methoxy,R² is hydrogen, R³ is alkylsulfonyl, and Ar is a mono or disubstitutedphenyl.General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1–17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1–40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4^(th) Edition) and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989). Theseschemes are merely illustrative of some methods by which the compoundsof this invention can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the arthaving referred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but-not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including the measurement of hysical constants andspectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

A person of ordinary skill in the art will have no difficulty, havingregard to that skill and this disclosure, in determining how tosynthesize compounds of this invention.

Preparation of Compounds of Formula I

Schemes A, B, C, and D describe methods to prepare the compounds ofFormula I.

Scheme A is the synthesis of a compound of Formula I wherein A is —S—,—S(O)—, or SO₂; R³ is —S(O)₀₋₂R¹² (wherein R¹² is alkyl); R is alkyl,and R² and Ar are as defined in the Summary of the Invention.

In Step 1, a quinolone of Formula 1 (wherein R is alkyl) is halogenatedwith an inorganic acid halide such as POCl₃ to give a chloroquinoline ofFormula 2. In general, the compounds of Formula 1 are commerciallyavailable or can be readily synthesized by those of ordinary skill inthe art, see e.g., DeRuiter et al, J. Med Chem., 29, 10; 2021–2028(1986).

In Step 2, the chloroquinoline is modified by displacement with athiolate ion of general formula NASR¹² (wherein R¹² is alkyl) to providea quinoline sulfide of Formula 3. Suitable solvents for the reaction arepolar aprotic solvents such as DMF, DMSO, HMPA, and the like. Thisreaction can also be carried out with compounds of Formula 2 wherein the2 position is a leaving group other than chlorine, such as for examplealkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy, arylcarbonyloxy,mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy, methoxy, orN,O-dimethylhydroxylamino.

In Step 3, oxidation of the quinoline sulfide of Formula 3 with asuitable amount of oxidizing agent, such as OXONE™, MCPBA, and the like,provides a quinoline sulfone of Formula 4. Suitable solvents for thereaction are alcohols (such as methanol and ethanol) or halogenatedsolvents (such as dichloromethane, chloroform, and the like).

In Step 4, the quinoline sulfoxide or the quinoline sulfone are coupledwith an aryl thiol of general formula ArSH to provide a compound ofFormula I wherein A is —S— and R³ is —SO₂R¹² wherein R¹² is alkyl.

In Step 5, the compound of Formula I wherein R³ is —SO₂R¹² may then beconverted to the quinoline sulfide of Formula I wherein R³ is —SR¹² bytreatment with a sodium thiolate of Formula NaSR¹² in suitable solventssuch as polar aprotic solvents, e.g. DMF, DMSO and the like.

As an additional step the compound of Formula I can be further oxidizedwith a suitable amount of OXONE™, MCPBA, and the like to provide acompound of Formula I wherein A is —S(O)— or —SO₂—. Similarly, oxidationcan provide a compound of Formula I, wherein R³ is S(O)R¹².

Using synthetic techniques well known in the art, the —OR (wherein R isalkyl) substituent at the 6-position of the quinoline can be convertedto any one of the other claimed substituents for R¹.

Scheme B is illustrative of the synthesis of a compound of Formula Iwherein A is —CH₂—, —C(O)—, CH(OH), or C═NOR⁴; R³ is —S(O)₀₋₂R¹²(wherein R¹² is alkyl); and R¹, R², and Ar are as defined in the Summaryof the Invention. An alternative synthesis of a compound of Formula Iwherein A is —CH₂— is described in Scheme D.

In Step 1, the quinoline sulfone of Formula 5 (wherein R is alkyl, seee.g. Hayashi et al., Chem. Abstr.; 87 167846; (1977)) is brominated withbromine. After stirring, the above reaction mixture is poured into asolution of a base (such as sodium bicarbonate and the like) and sodiumthiosulfate to provide a bromo quinoline sulfone of Formula 6. Suitablesolvents for this reaction are halogenated hydrocarbons, such asdichloromethane, dichloroethane, and the like.

In Step 2, the bromo quinoline sulfone 6 is treated with a thiolate ionof general formula NaSR¹² (wherein R¹² is alkyl) to provide a bromoquinoline sulfide of Formula 7. Suitable solvents for this reaction arepolar aprotic solvents such as DMF, DMSO, HMPA, tetraglyme, and thelike.

In Step 3, the bromo quinoline sulfide 7 is initially treated witht-BuLi. To this reaction mixture is added an aryl aldehyde of generalformula ArCHO to provide a secondary alcohol quinoline sulfide ofFormula 8. Suitable solvents for this reaction are Lewis bases such asTHF, diethyl ether, dioxane, and the like. This reaction is carried outat approximately −78° C. to room temperature.

At this point, one of two synthetic routes can be taken depending onwhat is desired as the substituent at R³.

In Step 4a, oxidation of the secondary alcohol quinoline sulfide ofFormula 8 with a suitable amount of oxidizing agent, such as OXONE™,MCPBA, and the like, provides a secondary alcohol quinoline sulfoxide ora secondary alcohol quinoline sulfone of Formula 9. Suitable solventsfor the reaction are alcohols, such as methanol, ethanol, and the like.

In Step 5a, oxidation of the secondary alcohol quinoline sulfoxide orthe secondary alcohol quinoline sulfone with a mild oxidizing agent suchas PCC, MnO₂, and the like, provides a compound of Formula I wherein Ais —C(O)— and R³ is —S(O)₁₋₂R¹². Suitable solvents for this reaction arehalogenated hydrocarbons, such as dichloromethane, dichloroethane, andthe like.

Using synthetic techniques well known in the art, the —OR (wherein R isalkyl) substituent at the 6-position of the quinoline can be convertedto any one of the other claimed substituents for R¹.

As an alternative, in Step 4b a Swern oxidation is used to oxidize thesecondary alcohol quinoline sulfide of Formula 8. In this method,oxidation of the alcohol is carried out with dimethyl sulfoxide andoxalyl chloride to provide a compound of Formula I wherein A is —C(O)—and R³ is —SR¹². Suitable solvents for the reaction are halogenatedhydrocarbons, such as dichloromethane, dichloroethane, and the like. InStep 5b compound of Formula I (wherein R³ is —S(O)₁₋₂R¹²) may beobtained by oxidation of the quinoline sulfide of Formula I (wherein R³is —SR¹²) with a suitable amount of oxidizing agent such as OXONE™,MCPBA, and the like

Again as an additional step using synthetic techniques well known in theart, the —OR (wherein R is alkyl) substituent at the 6-position of thequinoline can be converted to any one of the other claimed substituentsfor R¹.

As an additional alternative, condensation of a compound of Formula Iwith a hydroxylamine (R⁴ONH₂) gives a compound of Formula I wherein A is—C═NOR⁴.

In another alternative, an alcohol of Formula 8 or 9 can be reduced togive a compound of Formula I wherein A is —CH₂—. This reduction can beperformed, for example, by catalytic hydrogenation, under the reactionconditions of TFA/triethylsilane, or under radical processes.

Alternative Preparation of an Alcohol of General Formula 8:

An alternative synthesis of the alcohol of general Formula 8 may beachieved by halogenation of the quinoline N-oxide of Formula 10 with aninorganic acid halide such as POCl₃, to give the chloroquinoline ofgeneral Formula 11. Subsequently the chloroquinoline may be furtherbrominated to yield the 5-bromo-2-chloroquinoline of Formula 12 whichmay be further modified by displacement with a thiolate ion of generalformula NASR¹² to provide a quinoline bromide of general Formula 13. Thequinoline bromide may be converted to the quinoline nitrile of generalFormula 14 by Rosenmund-von Braun cyano-de-halogenation with cuprouscyanide, or by reaction with alkali cyanides in the presence of Pd(II)salts or under phase transfer conditions in the presence of a nickelcomplex, preferably with cuprous cyanide. The quinoline nitrile ofgeneral Formula 14 may be reduced with a metal hydride reducing agent,preferably with diisobutylaluminum hydride (DIBAL), and subsequentlytreated with a suitable organometallic aryl such as aryllithium toprovide the quinoline alcohol of general Formula 8.

Scheme C is illustrative the synthesis of a compound of Formula Iwherein A is —NR⁵— or —O—; R³ is —S(O)₀₋₂R¹² (wherein R¹² is alkyl); andR¹, R², and Ar are as defined in the Summary of the Invention.

In Step 1, the 8-nitroquinoline of Formula 15 (wherein R is alkyl, seee.g. Haskelberg et al., J. Org. Chem., 12, 434 (1947)) is brominatedwith bromine to provide a 5-bromo-8-nitroquinoline of Formula 16.Suitable solvents for this reaction are halogenated hydrocarbons, suchas dichloromethane, dichloroethane, and the like.

In Step 2, the 5-bromo-8-nitroquinoline is treated with a compound ofgeneral formula, Ar-AH (wherein A is —NR⁵ or —O—) to provide a8-nitroquinoline of Formula 17 (wherein A is —NR⁵or —O—).

In Step 3, the nitro group of the 8-nitroquinoline 17 is reduced using asuitable reducing agent (such as SnCl₂ and EtOH, palladium catalyzedhydrogenation, and the like) to provide an 8-aminoquinoline of Formula18.

In Step 4, the amino of the 8-aminoquinoline 18 is deaminated by methodswell known in the art. A preferred method may be achieved in a one stepby treatment with an alkyl nitrite in a suitable solvent such as DMF orboiling THF. This reaction provides the quinoline of Formula 19.

In Step 5, the quinoline of Formula 19 is treated with a peracid or withhydrogen peroxide to form the quinoline N-oxide of Formula 20. Suitablesolvents include acetic acid and the like.

In Step 6, the quinoline N-oxide 20 is treated with acetic anhydride anda base (such as NaOH, KOH, and the like) to provide a 2-quinolone ofFormula 21.

In Step 7, chlorine as leaving group L is introduced to the 2-quinolone21 by halogenation with an inorganic acid halide such as POCl₃, to givea chloroquinoline 21′. The leaving group L at the 2-position of thequinoline can also be, for example, alkanesulfonyloxy, arenesulfonyloxy,alkylcarbonyloxy, arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy, methoxy, orN,O-dimethylhydroxylamino.

In Step 8, the quinoline of formula 21′ is treated with a thiolate ionof general formula NaSR¹². This reaction provides a compound of FormulaI wherein R³ is —SR¹² (wherein R¹² is alkyl). Optionally, this compoundmay be oxidized with a suitable amount of oxidizing agent such as asOXONE™, MCPBA, and the like, to provide a compound of Formula I whereinR³ is —SOR¹² or —SO₂R¹²″ (wherein R¹² is alkyl). Suitable solvents forthe oxidation are alcohols, such as methanol, ethanol, and the like.

Using synthetic techniques well known in the art the —OR (wherein R isalkyl) substituent at the 6-position of the quinoline can be convertedto any one of the other claimed substituents for R¹.

Scheme D is illustrative of an alternative synthesis of a compound ofFormula I wherein A is CH₂; and R¹, R², and Ar are as defined in theSummary of the Invention. An alternative synthesis is described hereinin Scheme B.

The quinoline sulfone compound 22 wherein X is a halogen, morepreferably a bromide, may be treated with an optionally substitutedbenzyl metal bromide, wherein the metal is preferably zinc or magnesium,and more preferably zinc, in the presence oftetrakis(triphenylphosphine)palladium in an inert solvent such as THF toafford a compound of Formula I (R³═—SO₂R¹²).

Optionally the quinoline sulfone of Formula I (R³═—SO₂R¹²) may then beconverted to the quinoline sulfide I (R³═—SR¹²) by treatment with sodiumthiomethoxide in suitable solvents such as polar aprotic solvents, e.g.DMF, DMSO, HMPA, tetraglyme, and the like. The sulfide may be furtheroptionally oxidized with two equivalents of a suitable oxidizing agentsuch as OXONE™ to provide the quinoline sulfoxide of Formula I(R³═—SOR¹²).

Using synthetic techniques well known in the art the —OR (wherein R isalkyl) substituent at the 6-position of the quinoline can be convertedto any one of the other claimed substituents for R¹.

General Utility

The compounds of the invention are inhibitors of prostaglandin G/HSynthase I and II (COX I and COX II), especially COX II, in vitro, andas such are expected to possess both anti-inflammatory, and analgesicproperties in vivo. See, for example, Goodman and Gilmans's “ThePharmacological Basis of Therapeutics”, Ninth Edition, McGraw Hill, NewYork, 1996, Chapter 27. The compounds, and compositions containing them,are therefore useful as anti-inflammatory and analgesic agents inmammals, especially humans. They find utility in the treatment of fever,inflammation, and pain caused by conditions such as rheumatic fever,symptoms associated with influenza or other viral infections, low backand neck pain, dysmenorrhoea, headache, dental pain, sprains, strains,sports injuries, bursitis, tendonitis, myositis, synovitis, arthritis(rheumatoid arthritis and osteoarthritis), gout, ankylosing spondylitis,burns, or injuries. They maybe used to inhibit prostanoid-induced smoothmuscle contractions (e.g., in the treatment of dysmenorrhoea, prematurelabor, and asthma) and to treat autoimmune disorders (such as systemiclupus erythematosus and type I diabetes).

As inhibitors of prostaglandin G/H Synthase, the compounds of thisinvention are also expected to be useful in the prevention and treatmentof cancer, in particular colon cancer. It has been shown that COX-2 geneexpression is upregulated in human colorectal cancers and that drugsthat inhibit prostaglandin G/H Synthase are effective in animal modelsof cancer (Eberhart, C. E., et. al., Gastroenterology, 107, 1183–1188,(1994), and Ara, G. and Teicher, B. A., Prostaglandins, Leukotrienes andEssential Fatty Acids, 54, 3–16, (1996)). In addition, there isepidemiological evidence that shows a correlation between use of drugsthat inhibit prostaglandin G/H synthase and a reduced risk of developingcolorectal cancer, (Heath, C. W. Jr., et. al., Cancer, 74, No. 10,2885–8, (1994)).

The compounds of this invention are also expected to be useful in theprevention and treatment of Alzheimer's disease. Indomethacin, aninhibitor of prostaglandin G/H synthase, has been shown to inhibit thecognitive decline of Alzheimer's patients, (Rogers, J., et. al.,Neurology, 43, 1609, (1993)). Also, the use of drugs which inhibitprostaglandin G/H synthase has been linked epidemiologically with adelayed onset of Alzheimer's disease, (Breitner, J. C. S., et. al.,Neurobiology of Aging, 16, No. 4, 523, (1995) and Neurology, 44, 2073,(1994)).

Testing

The anti-inflammatory activity of the compounds of this invention may beassayed by measuring the ability of the compound to inhibit COX I andCOX II, especially COX II, in vitro, using a radiometric assay, asdescribed in more detail in Example 9. It may also be assayed by in vivoassays such as the Rat Carrageenan Paw and Rat Air-Pouch assays, asdescribed in more detail in Examples 10 and 11. The analgesic activityof the compounds of this invention may be assayed by in vivo assays suchas the Randall-Selitto assay and the rat arthritis pain model, asdescribed in Example 12.

Administration and Pharmaceutical Composition

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors.

Therapeutically effective amounts of compounds of Formula I may rangefrom approximately 0.005–10 mg per kilogram body weight of the recipientper day; preferably about 0.05–1 mg/kg/day. Thus, for administration toa 70 kg person, the dosage range would preferably be about 3.5 mg to 400mg per day.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal, or by suppository), orparenteral (e.g., intramuscular, intravenous, or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of, in general, a compound of Formula Iin combination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid administration, and do notadversely affect the therapeutic benefit of the compound of Formula I.Such excipient may be any solid, liquid, semi-solid or, in the case ofan aerosol composition, gaseous excipient that is generally available toone of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18th ed., 1990).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01–99.99 wt% of a compound of Formula I based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1–80 wt %.Representative pharmaceutical formulations containing a compound ofFormula I are described in Example 7.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 15-(2,4-Difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline101

Step 1

A solution of 1.7 g of 6-methoxy-2(1H)-quinolone (10 mmoles) in 25 mLPOCl₃ was refluxed for 2 hours. The reagent was removed under reducedpressure and the resulting gum dissolved in CH₂Cl₂. The solution waswashed with aqueous NaHCO₃ to remove remaining acid, dried over MgSO₄,and then evaporated to afford 2-chloro-6-methoxy-quinoline as a solid.

Step 2

The 2-chloro-6-methoxy-quinoline was dissolved in 30 mL DMF and treatedwith 3 g NaSMe. After stirring for 2 hours the mixture was poured intowater and extracted with ether. The ether was dried over MgSO₄ andevaporated to give 2-methylsulfanyl-6-methoxy-quinoline as a solid,(80–90% for the foregoing two steps).

Step 3

A solution of 6-methoxy-2-methylsulfanyl-quinoline (1.0 g, 5 mmoles) in100 mL 1:1 MeOH/THF was treated with a solution of 5 g OXONE™ in 50 mLwater and stirred for 2–3 hours until the oxidation is complete. Themixture is poured into water and extracted with EtOAc. The organic phaseis dried and evaporated to yield 2-methanesulfonyl-6-methoxy-quinolineas a crystalline white product.

Step 4

A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg, 1 mmole)and 2,4-difluorobenzenethiol (296 mg, 2 mmoles) was treated with PIFA(645 mg, 1.5 mmoles) and stirred for 30 min. The solution was pouredinto dilute NaCl solution and extracted with ethyl acetate (EtOAc). Theorganic layer was dried (MgSO₄) and evaporated. The resulting oil wascrystallized to yield5-(2,4-difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline101.; ([M+H]⁺)=382 The yield is typically 80–90%.

In Step 4 above, replacing 2,4-difluorobenzenethiol with the followingbenzenethiols gives the following compounds of Formula I:

4-fluorobenzenethiol gives5-(4-fluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 102;([M+H]⁺)=364;

4-chlorobenzenethiol gives5-(4-chloro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 103;([M+H]⁺)=380;

2-chlorobenzenethiol gives5-(2-chloro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 104;([M+H]⁺)=380;

2-chloro-4-fluorobenzenethiol gives5-(2-chloro-4-fluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline105; ([M+H]⁺)=398;

4-bromobenzenethiol gives5-(4-bromo-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 106;([M+H]⁺)=425;

2,4-dichlorobenzenethiol gives5-(2,4-dichloro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline107; ([M+H]⁺)=415;

2,3,4,5,6-pentafluorobenzenethiol gives2-methanesulfonyl-6-methoxy-5-(2,3,4,5,6)-pentafluorophenylsulfanyl-quinoline108; ([M+H]⁺)=436;

benzenethiol gives2-methanesulfonyl-6-methoxy-5-(phenyl)sulfanyl-quinoline 109;([M+H]⁺)=346;

4-methoxybenzenethiol gives2-methanesulfonyl-6-methoxy-5-(4-methoxy-phenylsulfanyl)-quinoline 110;([M+H]⁺)=376;

2-fluoro-4-methoxybenzenethiol gives5-(2-fluoro-4-methoxy-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline111; ([M+H]⁺)=394;

2-chloro-4-methoxybenzenethiol gives5-(2-chloro-4-methoxy-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline112; ([M+H]⁺)=410;

2-methoxy-4-fluorobenzenethiol gives5-(2-methoxy-4-fluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline113; ([M+H]⁺)=394; and

2,6-Difluorobenezenethiol gives5-(2,6-difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline114; ([M+H]⁺)=382.

Example 21-(2-Methanesulfonyl-6-methoxy-quinolin-5-yl)-1-(4-methoxy-phenyl)-methanone201

Step 1

A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg, 1 mmole )in CH₂Cl₂ was treated with 2 mmoles Br₂ and stirred for 1 day. Themixture was poured into a solution of NaHCO₃ and sodium thiosulfate. Theproduct was extracted with CH₂Cl₂. The organic layer was dried andevaporated to afford 5-bromo-2-methanesulfonyl-6-methoxy-quinoline, 287mg (91%), as white crystals.

Step 2

The 5-bromo-2-methanesulfonyl-6-methoxy-quinoline was dissolved in 20 mLDMF and treated with 3 eq NaSCH₃. After stirring 1 hour at roomtemperature the mixture was poured into water and extracted with ether.The crystalline product, 5-bromo-6-methoxy-2-methylsulfanyl-quinoline,was isolated in quantitative yield.

Step 3

A solution of 280 mg (1 mmole) of5-bromo-6-methoxy-2-methylsulfanyl-quinoline in 4 mL THF was cooled to−78° C. and treated with 1.5 mL of 1.5 M t-BuLi in pentane. Afterstirring for 1.5 hours, 1.5 eq of p-methoxybenzaldehyde was added andthe reaction allowed to warm to room temperature. After partitioningbetween EtOAc and water the product was purified by chromatography onsilica gel (1:3 EtOAc/hexane) to afford(6-methoxy-2-methylsulfanyl-quinolin-5-yl)-(4-methoxy-phenyl)methanol(120 mg, 35%).

Step 4

(6-methoxy-2-methylsulfanyl-quinolin-5-yl)-(4-methoxy-phenyl)methanolwas dissolved in 5 mL MeOH and treated with 1 g of OXONE™ in 5 mL water.After stirring 45 min. it was poured into water and the productextracted with CH₂Cl₂. The product(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-(4-methoxy-phenyl)methanolwas used directly in the next reaction.

Step 5

(2-Methanesulfonyl-6-methoxy-quinolin-5-yl)-(4-methoxy-phenyl)methanolwas dissolved in 20 mL CH₂Cl₂ and treated with 1.5 g each Celite® andPCC. After stirring 2 hours an additional gram of PCC was added. After afurther hour, the mixture was filtered to remove solids and the organicphase was washed with water. After drying and evaporation the product1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-1-(4-methoxy-phenyl)-methanone201 was purified by chromatography (1:2 EtOAc/hexane). It was isolatedas a foam (80 mg, 61% over two steps). ([M+H]⁺)=372;

In Step 3 above, replacing p-methoxybenzaldehyde with the followingbenzaldehydes gives the following compounds of Formula I:

2-chloro-4-methoxybenzaldehyde gives1-(2-chloro-4-methoxyphenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,202 ([M+H]⁺)=376;

3-chloro-2-fluoro-6-methoxy-benzaldehyde gives1-(3-chloro-2-fluoro-6-methoxy-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,208 ([M+H]⁺)=424;

3-bromo-2,6-difluoro-benzaldehyde gives1-(3-bromo-2,6-difluoro-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,209 ([M+H]⁺)=457; and

2,6-difluoro-benzaldehyde gives1-(2,6-difluoro-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,210 ([M+H]⁺)=378.

Alternatively the quinoline alcohol of Step 3 may be synthesized by thefollowing steps:

Step 1a:

A solution of 6-methoxyquinoline N-oxide (5.0 g, 29 mmol) in CHCl₃ (30mL) was treated by slow addition of POCl₃ (5.3 mL, 57 mmol) at 0° C. Themixture was heated at 80° C. for 14 hours. The mixture was cooled andpoured onto ice. After stirring for 30 min., the aqueous layer wasadjusted to pH 9 by Na₂CO₃ addition. The mixture was extracted withCH₂Cl₂. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave2.5g (46%) of 2-chloro-6-methoxyquinoline as a white solid, (M⁺)193(100).

Step 2a:

A solution of 2-chloro-6-methoxyquinoline (4.4 g, 22 mmol) in CH₂Cl₂ (60mL) was treated by slow addition of Br₂ (3.5 mL, 11 g, 68 mmol). After14 hours, the mixture was partitioned between NaCl and CH₂Cl₂. Theaqueous layer was extracted with CH₂Cl₂. The organic layer wasworked-up. HPLC (1:10 EtOAc/hexane) gave 6.1 g (99%) of5-bromo-2-chloro-6-methoxyquinoline as a light yellow solid, (M⁺)273(100).

Step 3a

A solution of 5-bromo-2-chloro-6-methoxyquinoline (6.2 g, 22 mmol) inDMF (70 mL) was treated with NaSMe (1.9 g, 27 mmol). After 6 hours, themixture was partitioned between NaCl and EtOAc. The aqueous layer wasextracted with EtOAc. The organic layer was worked-up. HPLC (1:10EtOAc/hexane) gave 6.1 g (98%) of5-bromo-6-methoxy-2-methylthioquinoline as a white solid, (M⁺) 283(100).

Step4a

A mixture of 5-bromo-6-methoxy-2-methylthioquinoline (6.1 g, 21 mmol)and CuCN (3.7 g, 41 mmol) in DMF (80 mL) was heated at 150° C. for 14hours. The mixture was cooled and treated sequentially with 2:1H₂O/ethylenediamine (15 mL). The mixture was extracted with 1:1EtOAc/hexane. The organic layer was worked-up. HPLC (1:8 EtOAc/hexane)gave 4.2 g (87%) of 5-cyano-6-methoxy-2-methylthioquinoline as a lightyellow solid, (M⁺) 230(100).

Step 5a:

A solution of 5-cyano-6-methoxy-2-methylthioquinoline (3.2 g, 14 mmol)in toluene (30 mL) was treated with a 1.5 M solution of DIBAL in toluene(14 mL, 21 mmol). The mixture was heated to 30° C. for 14 hours. Themixture was cooled to 0° C., quenched with saturated aqueous NaCl, andextracted with EtOAc (2×). The combined organic layer was worked-up.HPLC (1:8 EtOAc/hexane) gave 1.4 g (43%) of6-methoxy-2-methylthioquinoline-5-carboxaldehyde as a light yellowsolid, (M⁺) 233(100).

A solution of 4-fluorobromobenzene (0.15 g, 0.86 mmol) in THF (5 mL) wastreated with a 2.5 M solution of n-BuLi in hexane (0.36 mL, 0.90 mmol)at −78° C. After 20 min., compound6-methoxy-2-methylthioquinoline-5-carboxaldehyde (0.20 g, 0.86 mmol)inTHF (5 mL) was added. After an additional 30 min., the mixture wasallowed to warm to ambient temperature for 5 h. The reaction wasquenched with H₂O and extracted with EtOAc. The organic layer wasworked-up. HPLC (1:8 EtOAc/hexane) gave 0.19 g (67%) of5-(4-fluorophenylhydroxymethano)-6-methoxy-2-methylthioquinoline. as anoil, (M⁺) 329(100).

Oxidation of5-(4-fluorophenylhydroxymethano)-6-methoxy-2-methylthioquinoline withone equivalent of OXONE™ following steps 4 and 5 from Example 2 yielded:

1-(4-Fluoro-phenyl)-1-(2-methanesulfinyl-6-methoxy-quinolin-5-yl)-methanone211 ([M+H]⁺) 344.

Replacement in step 5a of fluorobromobenzene with the followingbromobenzenes and oxidation with one equivalent of OXONE™ gives thefollowing compounds of Formula I:

4-chlorobromobenzene gives1-(4-chloro-phenyl)-1-(2-methanesulfinyl-6-methoxy-quinolin-5-yl)-methanone212 ([M+H]⁺) 360;

4-ethoxybromobenzene gives1-(4-ethoxy-phenyl)-1-(2-methanesulfinyl-6-methoxy-quinolin-5-yl)-methanone,213 ([M+H]⁺) 370; and

3-chloro-2-fluoro-6-methoxybenzene gives 1-(3-chloro-2-fluoro-6-methoxy-phenyl)-1-(2-methanesulfinyl-6-methoxy-quinolin-5-yl)-methanone, 214([M+H]⁺)=408.

Oxidation of5-(4-fluorophenylhydroxymethano)-6-methoxy-2-methylthioquinoline withtwo equivalents of OXONE™ following steps 4 and 5 from Example 2yielded:

1-(4-fluoro-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,203. ([M+H]⁺) 360.

Similarly, replacement in step 5a of fluorobromobenzene with thefollowing bromobenzenes and oxidation with two equivalents of OXONE™give the following compounds of Formula I:

2-fluorobromobenzene gives1-(2-fluoro-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,204 ([M+H]⁺)=360;

2,4-Difluorobromobenzene gives1-(2,4-difluoro-phenyl)-1-(2-methanesulfonyl-4-methoxy-quinolin-5-yl)-methanone,205 ([M+H]⁺)=378;

4-Ethoxybromobenzene gives1-(4-ethoxy-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,.206([M+H]⁺)=386; and

4-Chlorobromobenzene gives1-(4-chloro-phenyl)-1-(2-methanesulfonyl-6-methoxy-quinolin-5-yl)-methanone,207 ([M+H]⁺)=376.

Example 35-(2,4-Difluoro-benzenesulfinyl)-2-methanesulfonyl-6-methoxy-quinoline301

5-(2,4-Difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline101 (230 mg) was dissolved in 9 mL (1:1:1 MeOH/THF/H₂O) and was treatedwith 1 gram of OXONE™. After 3 hours the mixture was partitioned betweenCH₂Cl₂ and water. The product was purified by chromatography (10%MeOH/CH₂Cl₂) to afford 110 mg of5-(2,4-difluoro-benzenesulfinyl)-2-methanesulfonyl-6-methoxy-quinoline301; ([M+H]⁺)=398.

Example 4 5-(4-Fluoro-phenylsulfanyl)-2-methanesulfonyl-quinolin-6-ol401

5-(4-Fluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 102 (1g) was dissolved in 5 mL DMF and treated with 500 mg LiCl and refluxedovernight. This mixture was partitioned between dilute HCl and EtOAc.The product was purfied by chromatography (1:1 EtOAc/hexane) to provide5-(4-fluoro-phenylsulfanyl)-2-methanesulfonyl-quinolin-6-ol; 401 (800mg); ([M+H]⁺)=350.

Example 52-Methanesulfonyl-6-trifluoromethanesulfonoxy-5-(4-fluorophenyl)sulfanyl-quinoline501

5-(4-Fluoro-phenylsulfanyl)-2-methanesulfonyl-quinolin-6-ol 401 (800 mg)was dissolved in 20 mL CH₂Cl₂ containing 1 mL triethylamine (NEt₃) andwas cooled to ice-bath temperature. Trifluoromethanesulfonic anhydride(0.5 mL) was added. After 1 hour the mixture was partitioned betweenCH₂Cl₂ and aqueous NaHCO₃. The product was purified by chromatography(3:1 hexanes/EtOAc) to provide2-methanesulfonyl-6-trifluoromethanesulfonoxy-5-(4-fluorophenyl)sulfanyl-quinoline501 (1 g); ([M+H]⁺)=482.

Example 6 5-(2,4-Difluoro-benzyl)-2-methanesulfonyl-6-methoxy-quinoline601

To the mixture of 3 g (9.5 mmol)2-methylsulfone-5-bromo-6-methoxyquinoline and 1 g oftetrakis(triphenylphosphine)palladium (0) in pressure tube undernitrogen was added 95 mL of 0.5M solution of 2,4-difluorobenzylzincbromide in THF. The reaction mixture in a pressure tube was stirred at65° C. for 12 hours.

The reaction mixture was partitioned between water and methylenechloride, the organic phase was washed three times with water, driedover MgSO₄, and the solvent was removed under vacuum.

The resulting yellow crystalline material was triturated with ether toyield 2.8 g of5-(2,4-difluoro-benzyl)-2-methanesulfonyl-6-methoxy-quinoline 601([M+H]⁺)=364.

Similarly, following the procedure described above, but replacing2,4-difluorobenzylzinc bromide with other appropriate substitutedbenzylzinc bromides the additional compounds of Formula (Ih) wherein Ais CH₂, were prepared:

-   4-fluorobenzyl zinc gives    5-(4-fluoro-benzyl)-2-methanesulfonyl-6-methoxy-quinoline; 602,    ([M+H]⁺)=346;-   2-fluorobenzyl zinc gives    5-(2-fluoro-benzyl)-2-methanesulfonyl-6-methoxy-quinoline; 603,    ([M+H]⁺)=346;-   4-ethoxybenzyl zinc gives    5-(4-ethoxy-benzyl)-2-methanesulfonyl-6-methoxy-quinoline; 604,    ([M+H]⁺)=372;-   4-methylbenzyl zinc gives    2-methanesulfonyl-6-methoxy-5-(4-methyl-benzyl)-quinoline; 605,    ([M+H]⁺)=342;-   4-methoxybenzyl zinc gives    2-methanesulfonyl-6-methoxy-5-(4-methoxy-benzyl)-quinoline; 606,    ([M+H]⁺)=358; and-   4-chlorobenzyl zinc gives    5-(4-chloro-benzyl)-2-methanesulfonyl-6-methoxy-quinoline; 607,    ([M+H]⁺)=362.

Alternatively,(2,4-difluoro-benzyl)-2-methanesulfonyl-6-methoxy-quinoline 601 (363 mg)in 8 mL DMF was treated with 10 mmoles NaSMe, and stirred 30 min. It waspartitioned between water and ether . The organic phase was evaporatedto yield 5-(2,4-difluoro-benzyl)-6-methoxy-2-methylsulfanyl-quinoline,608 ([M+H]⁺)=332. The resulting sulfide was dissolved in 10 mL 1:1MeOH/THF and 0.5 mmole OXONE™ in 2 mL water was added. After 3 hours thesolution was poured into water and extracted with CH₂Cl₂. The product5-(2,4-difluoro-benzyl)-2-methanesulfinyl-6-methoxy-quinoline 609 waspurified by PTLC on silica gel (1:1 hexane/EtOAc) to obtain 255 mgproduct ([M+H]⁺)=348.

Example 7 5-(2,4-Difluoro-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline701

Step 1:

2,4,-Difluorophenol (3.7 g, 28.6 mmol) was added to a solution of KOH(1.6 g, 28.6 mmol) in 40 mL of 2-ethoxyethanol, stirred for 10 min. atroom temperature under N₂, followed by addition of5-bromo-6-methoxy-8-nitroquinoline. The mixture was refluxed for 12hours, stirred at room temperature for 6 hours and kept in therefrigerator overnight. The solvent was removed under vacuum; theresidue was purified using a Biotage system, eluting with 20%EtOAc/Hexane. The product was crystallized from ethanol to yield 1.6 g(22.2%) of yellow crystals of5-(2,4-difluoro-phenoxy)-6-methoxy-8-nitro-quinoline.

Step 2:

To a solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-8-nitro-quinoline(1.36 g, 4.1 mmol) in 30 mL of THF was added an aqueous solution ofsodium hypophosphite (2.7 g, 31 mmol in 10 mL H₂O). The reaction mixturewas degassed under N₂, treated with Pd/C (˜1 g), and stirred at roomtemperature under N₂ for 1 hour. The reaction mixture was filteredthrough Celite®, and washed with 1N NaOH solution followed by water. Theorganic layer was dried over MgSO₄, and the solvent removed to give 0.9g (75%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinolin-8-ylamine.

Step 3:

A solution of 2.4 mL HCl in 24 mL H₂O was heated to the boiling pointand poured into 2.4 g (0.008 mol) of5-(2,4-difluoro-phenoxy)-6-methoxy-quinolin-8-ylamine, then stirredwhile hot to dissolve as much solid as possible. The solution was cooledin an ice-salt mixture. When the temperature reached 15° C., 2.5 mL ofconc. HCl were added to the reaction mixture. At 10° C. a solution ofNaNO₂ (1.1 g, 0.016 mol in 2 mL of water) was added dropwise during 10min. The reaction mixture was stirred at 5–10° C. for 30 min., treatedwith ice-cold 30% H₃PO₄, and cooled at 0° C. overnight. After stirringfor an additional 8 hours. at room temperature, the reaction mixture wasneutralized with 1N NaOH, extracted with CH₂Cl₂, and the organic layerwas dried (MgSO₄). Solvent removal, followed by HPLC, eluting with10–20% EtOAc/Hexane gave 1.5 g (66%) of5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline, which crystallized at roomtemperature.

Step 4:

The solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline in glacialacetic acid containing 4 ml hydrogen peroxide was stirred at 80–85° C.for 18 hours. After cooling the reaction mixture was neutralized withaqueous ammonia, and the resultant precipitate was filtered and washedwith water. The aqueous layer was extracted with dichloromethane, andthe organic layer was dried (MgSO₄). Evaporation gave 1.3 g (68%) of5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline N-oxide as a beigecrystalline material.

Step 5:

5-(2,4-Difluoro-phenoxy)-6-methoxy-quinoline N-oxide (1.35 g, 4.5 mmol)was mixed with 5 mL of acetic anhydride and stirred at 75° C. for 22hours. The reaction mixture was poured on ice, neutralized with aqueousammonia, and the resultant precipitate was filtered and washed withwater. The aqueous layer was extracted with dichloromethane and theorganic extract was dried over MgSO₄. The solvent was removed undervacuum. The dry residue, combined with the filtered precipitate, wasdissolved in a minimum amount of CH₂Cl₂ and purified using a Biotagesystem, eluting with 10–30% EtOAc/hexane to give 0.3 g (22.2%) of5-(2,4-difluoro-phenoxy)-6-methoxy-1H-quinolin-2-one.

Step 6:

A solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-1H-quinolin-2-onederivative (0.3 g) in 10 mL of POCl₃ was refluxed for 1.5 hours. POCl₃was removed under vacuum, the residue was stirred with saturated aqueoussodium bicarbonate solution, the product was extracted with methylenechloride, and the organic layer was dried (MgSO₄). Solvent removal gave0.28 g (87.5%) of 2-chloro-5-(2,4-difluoro-phenoxy)-6-methoxy-quinolineas pure white crystals.

Step 7:

A solution of 2-chloro-5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline(0.28 g) in 10 mL of DMF was treated with 1 equivalent of NaSCH₃ andstirred for 30 min. at room temperature. The reaction mixture waspartitioned between water and methylene chloride, the organic layer wasdried over MgSO₄, the solvent was evaporated in vacuum, and theremaining DMF was removed under vacuum to yield 0.25 g of5-(2,4-difluoro-phenoxy)-6-methoxy-2-methylsulfanyl-quinoline 712, aswhite crystals ([M+H]⁺)=334.

Step 8:

A solution of 0.25 g of5-(2,4-difluoro-phenoxy)-6-methoxy-2-methylsulfanyl-quinoline in 10 mLof methanol was treated with aqueous OXONE™ solution (1.3 g in 5 mL H2O)and stirred for 2 hours at room temperature. The reaction mixture waspartitioned between water and dichloromethane, the organic layer wasdried (MgSO₄), and the solvent was removed under vacuum. The solidresidue was dissolved in a minimum amount of dichloromethane and washedthrough a silica gel plug to remove the baseline impurities. Elutionwith 30% EtOAc/hexane yielded 0.11 g (38%) of5-(2,4-difluoro-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline 701([M+H]⁺)=366, as white crystals.

Similarly, following the procedure described above, but replacing2,4,-difluorophenol with other appropriate substituted phenols theadditional compounds of Formula (Ih) wherein A is CH₂, were prepared:

2-Fluoro-4-methanesulfonyl-phenol gives5-(2-fluoro-4-methanesulfonyl-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline,702 ([M+H]⁺)=426;

4-Fluorophenol gives5-(4-fluoro-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline, 703([M+H]⁺)=348;

2-Chloro-4-methoxy-phenol gives5-(2-chloro-4-methoxy-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline,704 ([M+H]⁺)=394;

4-Ethoxy-phenol gives5-(4-ethoxy-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline, 705([M+H]⁺)=374;

Phenol gives 2-methanesulfonyl-6-methoxy-5-phenoxy-quinoline, 706([M+H]⁺)=330;

2-Fluoro-phenol gives5-(2-fluoro-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline, 707([M+H]⁺)=348;

2,6-Difluoro-phenol gives5-(2,6-difluoro-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline, 708([M+H]⁺)=366, and

2-Fluoro-6-methanesulfonyl-phenol gives5-(2-fluoro-6-methanesulfonyl-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline,709 ([M+H]⁺)=426.

Alternatively, following the procedure described above, but using one anequivalent of OXONE™ in step 8, the additional compounds of Formula (I)wherein A is —O—, and R3 is —SOR¹² were prepared:

5-(2,4-Difluoro-phenoxy)-2-methanesulfinyl-6-methoxy-quinoline, 710([M+H]⁺)=349; and

5-(4-Fluoro-phenoxy)-2-methanesulfinyl-6-methoxy-quinoline 711([M+H]⁺)=332

Example 8

The following are representative pharmaceutical formulations containinga compound of Formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilledwater q.s. to 100 mL

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 0.4 mg sodium acetatebuffer solution, 0.4 M 2.0 mL HCl (1N) or NaOH (1N) q.s. to suitable pHwater (distilled, sterile) q.s. to 20 mL

Example 9 Inhibition of COX I and COX II In Vitro

The COX I and COX II inhibitory activity of compounds of this inventionin vitro was determined using partially purified COX I and COX IIenzymes, prepared as described in J. Barnett et. al., Biochim Biophys.Acta, 1209, 130–139 (1994).

COX I and COX II samples were diluted with Tris-HCl buffer (50 mMTris-HCl, pH 7.9) containing 2 mM EDTA and 10% glycerol andreconstituted by incubating first with 2 mM phenol for 5 minutes andthen with 1 micromolar hematin for an additional 5 minutes. 125 μl ofthe reconstituted COX I or COX II enzyme were preincubated for 10minutes at room temperature in a shaking water bath with the compoundsof the invention dissolved in 2–15 μl of DMSO or the carrier vehicles(control samples). The enzyme reaction was initiated by adding 25 μl of1-[14 C]arachidonic acid (80,000–100,000 cpm/tube; 20 micromolar finalconcentration) and the reaction was allowed to continue for anadditional 45 seconds. The reaction was terminated by adding 100 μl of2N HCl and 750 μl water. An aliquot (950 μl) of the reaction mixture wasloaded onto a 1 mL C₁₈ Sep-Pak column (J. T. Baker, Phillipsburg, N.J.)which had been previously washed with 2–3 mL methanol and equilibratedwith 5–6 mL distilled water. Oxygenated products were quantitativelyeluted with 3 mL of acetonitrile/water/acetic acid (50:50:0.1, v/v) andthe radioactivity in the eluate determined in a scintillation counter.

Compounds of this invention were active in this assay for COX II.

The COX inhibitory activities (expressed as IC₅₀, the concentrationcausing 50% inhibition of the COX enzyme being assayed) of someexemplary compounds of the invention were:

COX I COX II CPD # IC₅₀, μM IC₅₀, μM 101 >40 <0.20 104 >40 <0.20 105 >40<0.20 106 >40 <0.30 107 >40 <0.30

Example 10 Anti-Inflammatory Activity

The anti-inflammatory activity of compounds of this invention wasdetermined by measuring the inhibition of carrageenan-induced paw edemain the rat, using a modification of the method described in Winter C. A.et al., “Carrageenan-Induced Edema in Hind Paw of the Rat as an Assayfor Anti-inflammatory Drugs” Proc. Soc. Exp. Biol. Med. 111, 544–547,(1962). This assay has been used as a primary in vivo screen foranti-inflammatory activity of most NSAIDs, and is considered predictiveof human efficacy. Briefly, test materials were administered orally tofemale rats in a volume of 1 mL prepared as solutions or suspensions inan aqueous vehicle containing 0.9% sodium chloride, 0.5% sodiumcarboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol and97.3% distilled water. Control rats received vehicle alone. After 1 h0.05 mL of a 0.5% solution of Carrageenan (Type IV Lambda, SigmaChemical Co.) in 0.9% saline was injected into the subplantar region ofthe right hind paw. Three hours later the rats were euthanized in acarbon dioxide atmosphere; hind paws were removed by severing at thetatso-crural joint; and the left and right paws were weighed. Theincrease in weight of the right paw over the left paw was obtained foreach animal and the mean increases were calculated for each group. Theanti-inflammatory activity of the test materials is expressed as thepercent inhibition of the increase in hind paw weight of the test grouprelative to the vehicle dosed control group.

Compounds of this invention were active in this assay.

Example 11 Inhibition of Eicosanoid Synthesis In Vivo

The activity of compounds of this invention in inhibiting in vivoeicosanoid (prostaglandin E₂) synthesis in inflamed tissues wasdetermined by the carrageenan-induced inflammation (air-pouch model) inrats, using a modification of the method described in Futaki, M., etal., “Selective Ihibition of NS-398 on prostanoid production in inflamedtissue in rat Carrageenan Air-pouch Inflammation” J. Pharm. Pharmacol.45, 753–755, (1993) and Masferrer, J. L., et al.; “Selective Inhibitionof inducible cyclooxygenase 2 in vivo is Antiflammatory andNonulcerogenic” Proc. Natl. Acad. Sci. USA. 91, 3228–3232, (1994). Inthis assay, an air-pouch is created in the rat and the PGE₂ levels inthe air-pouch exudate are measured by enzyme immunoassay. Briefly, malerats were anesthetized using a 60:40 CO₂:O₂ mixture and subsequentlyinjected subcutaneously with 20 mL of sterilized air, under asepticconditions, in the proximal area of the dorsum. This injection ofsterile air causes the creation of a subcutaneous “air pouch”. The nextday, a further 10 mL of sterile air was injected into the previouslyformed pouch using the same technique. The test materials wereadministered orally in a volume of 1 mL/100 g body weight as solutionsor suspensions in an aqueous vehicle containing 0.9% sodium chloride,0.5% sodium carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzylalcohol and 97.3% water. Control rats received vehicle alone. After 30minutes, 5 mL of a 0.5% solution of carrageenan (Sigma, Lambda Type IV)was injected into the air pouch. The rats were euthanized 3 or 6 h afterthe compound administration. 10 mL of a solution containing 10 μg/l ofindomethacin and 5.4 mM EDTA in 0.9% sterile saline was injected intothe air pouch; the air pouch was cut open; and the exudate washarvested. The total exudate volume was recorded, and the samples wereanalyzed for PGE₂ and 6-keto PGF₁ by ELISA (Titerzyme®, PerSeptiveDiagnostics, Boston, Mass.) and TxB₂ by radioimmuno assay (New EnglandNuclear Research, Boston Mass., Catalog No. NEK-037), according to themanufacturer's directions.

The mean concentrations of PGE₂ were calculated for each group. Theanti-inflammatory activity of test materials is expressed as the percentinhibition of PGE₂ formation in the test group relative to the controlgroup.

Compounds of this invention were active in this assay.

Example 12 Analgesic Activity

The analgesic activity of the compounds of this invention may bedetermined by using a modification of the method described in Randall,L. O., and Selitto, J. J., “A Method for Measurement of AnalgesicActivity on Inflamed Tissue”, Arch. Int. Pharmacodyn., CXI, 4, 409,(1957) and Gans, et. al., “Anti-Inflammatory and Safety Profile of DuP697, a Novel Orally Effective Prostaglandin Synthesis Inhibitor”, J.Pharmcol. Exp. Ther., 254, No. 1, 180, (1990). In this assay, the maleSprague Dawley rats were injected with 0.1 mL of 20% brewer's yeast indeionized water (Sigma, St. Louis) in the subplantar region of the lefthind foot. After 2 h, the test materials were administered orally in avolume of 1 mL/100 g body weight as solutions or suspensions in anaqueous vehicle containing 0.9% sodium chloride, 0.5% sodiumcarboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol and97.3% water. Control rats received vehicle alone. After 1 h, the hindpawwas placed on the platform of a Basile Analgesy-Meter (Ugo BiologicalResearch Apparatus, Italy, Model # 7200) and mechanical force wasapplied to the dorsum of the rat's hindpaw. Compounds of the inventionwere active in this assay.

The analgesic activity of compounds of this invention may also bedetermined by using an adjuvant-induced arthritis pain model in the rat,where pain is assessed by the animal's vocal response to the squeezingor flexing of an inflamed ankle joint, as described in Winter C. A. andNuss, G. W., “Treatment of Adjuvant Arthritis in rats withAntiinflammatory Drugs”, Arthritis Rheum., 9, 394–403, (1966) andWinter, C. A., Kling P. J., Tocco, D. J., and Tanabe, K., “Analgesicactivity of Diflunisal [MK-647; 5-(2,4-Difluorophenyl)salicylic acid] inRats with Hyperalgesia Induced by Freund's Adjuvant”, J. Pharmacol. Exp.Ther., 211, 678–685, (1979).

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication- or publication were so individually denoted.

1. A compound selected from the group of compounds represented byFormula I:

wherein: A is a —CH₂—, CH(OH), —C(O)—, C═NOR⁴, —NR⁵—, —O—, —S—, —S(O)—,or —S(O)₂—, where R⁴ is hydrogen or alkyl and R⁵ is hydrogen, alkyl, oracyl; Ar is an optionally substituted phenyl; R¹ is —OSO₂R¹¹ where R¹¹is selected from alkyl, cycloalkyl, and haloalkyl; R² is hydrogen,alkyl, alkenyl, alkoxy, hydroxy, halo, haloalkyl, heteroalkyl,alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, nitro, cyano, or —NR⁹R¹⁰where R⁹ and R¹⁰ are each independently selected from hydrogen, alkyl,and acyl; and R² represents substitution at any one of carbons C3, C4,C7 or C8; R³ is —SR¹², SOR¹², SO₂R¹², or SO₂NR¹³R¹⁴ wherein, R¹² isalkyl, hydroxyalkyl, alkoxyalkyl aminoalkyl, mono or dialkylaminoalkyl,carboxyalkyl, or alkoxycarbonylalkyl; R¹³ is hydrogen or alkyl, and R¹⁴is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, bydroxyalkyl,alkoxyalkyl, alkoxycarbonylalkyl, aminoalkyl, aryl, or aralkyl; or R¹³and R¹⁴ together with the nitrogen atom to which they are attached forma heterocycloamino group; and pharmaceutically acceptable salts thereof.2. A compound of claim 1 wherein A is —S—.
 3. A compound of claim 2wherein R² is hydrogen or methyl; and R³ is S(O)₀₋₂R¹² where R¹² isalkyl.
 4. A compound of claim 3 wherein Ar is unsubstituted phenyl.
 5. Acompound of claim 3 wherein Ar is 4-substituted phenyl or 2-substitutedphenyl.
 6. A compound of claim 3 wherein Ar is a disubstituted phenyl.7. A compound of claim 3 wherein Ar is optionally substituted at one ormore positions with a substituent or substituents independently selectedfrom the group consisting of fluoro, chloro, bromo, ethoxy, and methoxy.8. A compound of claim 1 wherein A is —C(O)—.
 9. A compound of claim 8wherein R² is hydrogen or methyl; and R³ is S(O)₀₋₂R¹² where R¹² isalkyl.
 10. A compound of claim 9 wherein Ar is unsubstituted phenyl. 11.A compound of claim 9 wherein Ar is 4-substituted phenyl or2-substituted phenyl.
 12. A compound of claim 9 wherein Ar is adisubstituted phenyl.
 13. A compound of claim 9 wherein Ar is optionallysubstituted at one or more positions with a substituent or substituentsindependently selected from the group consisting of fluoro, chloro,bromo, ethoxy, and methoxy.
 14. A compound of claim 1 wherein A is—CH₂—.
 15. A compound of claim 14 wherein R² is hydrogen or methyl; andR³ is S(O)₀₋₂R¹² where R¹² is alkyl.
 16. A compound of claim 15 whereinAr is unsubstituted phenyl.
 17. A compound of claim 15 wherein Ar is4-substituted phenyl or 2-substituted phenyl.
 18. A compound of claim 15wherein Ar is a disubstituted phenyl.
 19. A compound of claim 15 whereinAr is optionally substituted at one or more positions with a substituentor substituents independently selected from the group consisting offluoro, chloro, bromo, ethoxy, and methoxy.
 20. A compound of claim 1wherein A is —O—.
 21. A compound of claim 20 wherein R² is hydrogen ormethyl; and R³ is S(O)₀₋₂R¹² where R¹² is alkyl.
 22. A compound of claim21 wherein Ar is unsubstituted phenyl.
 23. A compound of claim 21wherein Ar is 4-substituted phenyl or 2-substituted phenyl.
 24. Acompound of claim 21 wherein Ar is a disubstituted phenyl.
 25. Acompound of claim 21 wherein Ar is optionally substituted at one or morepositions with a substituent or substituents independently selected fromthe group consisting of fluoro, chloro, bromo, ethoxy, and methoxy. 26.A process for preparing a compound selected from the group of compoundsof claim 1, which comprises reacting a compound of general Formula

wherein R¹, R², and R¹² are as defined in claim 1, with a compound ofgeneral formula ArSH, to provide a compound of Formula I:

wherein Ar, R¹, R², and R¹² are as defined in claim
 1. 27. A process forpreparing a compound selected from the group of compounds of claim 1,which comprises reacting a compound of general Formula

wherein R¹, R², and R¹², are as defined in claim 1, with an oxidizingagent to provide a compound of Formula I:

wherein Ar, R¹, R², and R¹² are as defined in claim
 1. 28. A process forpreparing a compound selected from the group of compounds of claim 1,which comprises reacting a compound of general formula

wherein A is —NR⁵ or —O, and L is a leaving group such as a halogengroup as defined in the specification, with a compound of generalformula NaSR¹², followed by optional oxidation to provide a compound ofFormula I:


29. A process for preparing a compound selected from the group compoundsof claim 1, which comprises reacting a compound of general formula

wherein X is a halogen, with an aralkyl anion compound to provide acompound Formula I: